title: Functional analysis of purine nucleoside phosphorylase as a key enzyme in ribavirin metabolism.
abstract: Ribavirin is a purine nucleoside analogue that possesses potent anti-hepatitis C virus activity, and it has long been considered likely that ribavirin undergoes a first-pass metabolism at the small intestine. Although purine nucleoside phosphorylase (PNP) is assumed to be involved in this metabolism, this has not been conclusively demonstrated. Furthermore, no pharmacogenomic studies related to PNP-mediated ribavirin phosphorolysis have previously been conducted. In this study, we sought to identify the role of PNP in ribavirin phosphorolysis in the human small intestine, and to clarify the effect of the single nucleotide polymorphism (rs1049564) on PNP's ribavirin phosphorolysis activity. The results of our investigations show that PNP is abundantly expressed in the human small intestine, and that intestinal ribavirin phosphorolysis is severely inhibited by ganciclovir, a PNP-inhibitor. Therefore, PNP is likely to play a primary role in the ribavirin phosphorolysis in the human small intestine. On the other hand, the results of our attempt to clarify the function of rs1049564 show that it does not affect PNP's ribavirin phosphorolysis activity. We believe that the present study will facilitate further pharmacogenomic and biochemical characterization of PNP as a key metabolic enzyme of ribavirin.
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Furihata
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kishida
authors.forename: Hanae
authors.initials: H
authors.lastname: Sugiura
authors.forename: Atsuko
authors.initials: A
authors.lastname: Kamiichi
authors.forename: Minami
authors.initials: M
authors.lastname: Iikura
authors.forename: Kan
authors.initials: K
authors.lastname: Chiba
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015774:Ganciclovir / Q000494:pharmacology; D005838:Genotype; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology*; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012254:Ribavirin / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D012254:Ribavirin; D011683:Purine-Nucleoside Phosphorylase; D015774:Ganciclovir